Alzheimer's disease (AD) is a disease which frequently occurs in middle-aged or older people and whose major symptom is cognitive impairment (including memory disorder, orientation disturbance, learning disorder, attention disorder, spatial cognitive impairment, problem-solving impairment, etc.). Symptoms of this disease progress over several years, during which there often appear problem behaviors such as persecutory delusion, hallucination, offensive language, violence, wandering, and unclean behavior. This causes unwanted effects not only on patients themselves, but also on those around them including their family members and physicians, nurses, therapists, etc.
Alzheimer's disease has three pathological features, i.e., senile plaques (Aβ deposition), neurofibrillary tangles (tau deposition), and neuronal loss. Many studies have indicated that Aβ deposition occurs prior to tau deposition and neuronal changes, and the “amyloid hypothesis” has become widely known, which states that prevention of Aβ deposition would allow some avoidance of the subsequent events, i.e., tau accumulation in neurons, loss of neurons and so on.
Based on the amyloid hypothesis, Aβ peptide vaccine therapy has been proposed as a radical therapy for Alzheimer's disease (Non-patent Document 1). This vaccine therapy is based on the experiments in mice, in which the mice were externally administered with the Aβ peptide together with an immune activator (adjuvant) to induce in vivo production of anti-Aβ antibody to thereby reduce Aβ accumulation in the brain.
However, clinical trials in humans have been discontinued because of side effect problems, such as meningoencephalitis developed in cases receiving real drugs.
Following these clinical trials, further development has proceeded in an attempt to design vaccine formulations which do not cause encephalitis. The Aβ peptide is known to induce Th1 responses primarily through its C-terminal fragment and Th2 responses through its N-terminal fragment. Thus, clinical trials have been conducted for vaccines comprising an N-terminal fragment of Aβ attached to a carrier protein (Non-patent Document 2).
However, it was still difficult to overcome side effects including encephalitis.
For this reason, DNA vaccine therapy has been developed as a new vaccine therapy for Alzheimer's disease, which is an alternative to these Aβ peptide vaccines. Moreover, the inventors of the present invention have developed DNA vaccines which are effective for elimination of deposited Aβ and are also highly safe (Non-patent Document 3). A known example of the DNA vaccines developed by the inventors is an IgL-Aβ-Fc vaccine (Patent Document 1).
Recent studies have been indicating that there are various subspecies of neurotoxic Aβ. Aβ oligomers, which are most intensively analyzed, can be divided into two major types, i.e., those of low-molecular-weight type assembled from 2, 3 or 4 molecules and those of high-molecular-weight type assembled from 12 or more molecules. Moreover, strong neurotoxicity is also observed in pEAβ3-42, which is N-terminally truncated and pyrrole-derivatized by post-translational modification (Non-patent Documents 4 and 5). Furthermore, some findings are also being obtained, which suggest that other molecules such as ABri (Non-patent Document 6) and ADan, which have high amyloid aggregation propensity although their amino acid sequences are completely different from that of Aβ, are also involved in the onset of Alzheimer's disease.